Cycloalkyl and heterocycloalkyl substituted benzothiophenes as therapeutic agents

Abstract

The present invention provides benzo[b]thiophenes of Formula I: wherein R 1 , R 2 , R 3 , and L have any of the values defined therefor in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cardiovascular diseases, and cancers. Also provided are pharmaceutical compositions comprising one or more compounds of Formula I.

1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
 wherein R and R 3  are selected from the group consisting of: 
 (i) R 2  is methoxy and R 3  is methyl or methoxy; and  
 (ii) R 2  is methyl and R 3  is methoxy;  
 
 wherein L is absent, or a C 1 -C 4 -alkylene;  
 wherein R 1  is C 3 -C 8  cycloalkyl, a C 5 -C 8  cycloalkenyl, a 4- to 6-membered heterocycloalkyl, a tetrahydropyranyl, a piperidinyl, a oxetanyl, a tetrahydrofuranyl, a bicyclo[2.2.1]heptyl, or a decahydro-naphthalenyl,  
 wherein R 1  can be optionally substituted with 4 methyls, a C 1 -C 2  alkylene-6-membered heterocycloalkyl, or from 1 to 3 substitutents independently selected from the group consisting of: 
 C 1 -C 4  alkyl, methyl, tert-butyl, C(O)CH 3 , C(O)O—C 1 -C 4 alkyl, CH 2 -phenyl, a C 5 -C 6  cycloalkyl, Cl, Br, F, —CF 3 , —OH, —OCF 3 , and O—C 1 -C 6 alkyl.  
 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  is methoxy, and R 3  is methyl.  
     
     
         3 . The compound of  claim 2 , wherein R 1  is an optionally substituted group selected from the group consisting of: 
 tetrahydropyranyl, C 6 -cycloalkyl, C 7 -cycloalkyl, and piperidinyl.    
     
     
         4 . The compound of  claim 2 , wherein said compound is selected from the group consisting of: 
 5-Methoxy-6-methyl-3-(tetrahydro-pyran-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    5-Methoxy-6-methyl-3-(3,3,5,5-tetramethyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    5-Methoxy-6-methyl-3-(3,3,5-trimethyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    3-(3,3-Dimethyl-cyclohexyloxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    3-Cyclohexyloxy-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    5-Methoxy-6-methyl-3-(3-methyl-cyclohexyloxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    3-Cycloheptyloxy-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    3-[5-methoxy-6-methyl-2-(2Htetrazol-5-ylcarbamoyl)-benzo[b]thiophen-3-yloxy-piperdine-1-carboxylic acid tert-butyl ester;    3-(3-Cyclohexyl-propoxy)-5-Methoxy-6-methyl-benzo[b}thiophene-2-carboxylic acid (2H-tetrazol-5-yl)amide;    3-(1-Acetyl-piperidin-4-yloxy)-5-methoxy-6-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    4-[5-Methoxy-6-methyl-2-(2H-tetrazol-5-ylcarbamoyl)-benzo[b]thiophene-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester; and    5-Methoxy-6-methyl-3-(1-methyl-cyclopropylmethoxy)-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide.    
     
     
         5 . The compound of  claim 1 , wherein R 2  is methoxy and R 3  is methoxy.  
     
     
         6 . The compound of  claim 5 , wherein R 1  is an optionally substituted group selected from the group consisting of: 
 C 3 -cycloalkyl, C 6 -cycloalkyl, C 6 -cycloalkenyl, and bicyclo[2.2.1]heptyl.    
     
     
         7 . The compound of  claim 5 , wherein said compound is selected from the group consisting of: 
 3-(2,2-Dichloro-cyclopropylmethoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    3-Cyclohexyloxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    3-(4-tert-Butyl-cyclohexyloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide;    5,6 Dimethoxy-3-(3-methyl-bicyclo[2.2.1]hept-2-ylmethoxy)-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;    3-(Cyclohex-3-enylmethoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide;    3-(3,5-Dimethyl-cyclohexloxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide; and    3-(3-Cyclohexyl-propoxy)-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (1H-tetrazol-5-yl)-amide.    
     
     
         8 . The compound of  claim 1 , wherein R is methyl and R 3  is methoxy.  
     
     
         9 . The compound of  claim 8 , wherein R 1  is an optionally substituted C 6 -cycloalkyl.  
     
     
         10 . The compound of  claim 8 , wherein said compound is 3-Cyclohexyloxy-6-methoxy-5-methyl-benzo[b]thiophene-2-carboxylic acid (2H-tetrazol-5-yl)-amide.  
     
     
         11 . A method of treating a subject comprising: 
 administering, to a subject suffering from a disease selected from the group consisting of: rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases, and autoimmune diseases, a pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.    
     
     
         12 . The method of  claim 11  wherein said disease is rheumatoid arthritis.  
     
     
         13 . A method of treating a subject comprising: 
 administering, to a subject suffering from a disease selected from the group consisting of: cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, a pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.    
     
     
         14 . A method of treating a subject comprising: 
 administering, to a subject suffering from a disease selected from the group consisting of: cancer, breast cancer, gliobastoma, endometrial carcinoma, heptocellular carcinoma, colon cancer, lung cancer, melanoma, renal cell carcinoma, thyroid carcinoma, small cell lung cancer, squamous cell lung carcinoma, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, leukemia, cell lymphoma, and lymphoproliferative disorders, a pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.    
     
     
         15 . A method of treating a subject comprising: 
 administering, to a subject suffering from a disease selected from the group consisting of: type II diabetes, respiratory diseases, bronchitis, asthma, and chronic obstructive pulmonary disease, a pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.    
     
     
         16 . A pharmaceutical composition comprising: 
 a therapeutically effective amount of a compound of Formula I:                          or a pharmaceutically acceptable salt thereof;    wherein R 2  and R 3  are selected from the group consisting of: 
 (i) R 2  is methoxy and R 3  is methyl or methoxy; and  
 (ii) R 2  is methyl and R 3  is methoxy;  
   wherein L is absent, or a C 1 -C 4 -alkylene;    wherein R 1  is C 3 -C 8  cycloalkyl, a C 5 -C 8  cycloalkenyl, a 4- to 6-membered heterocycloalkyl, a tetrahydropyranyl, a piperidinyl, a oxetanyl, a tetrahydrofuranyl, a bicyclo[2.2.1]heptyl, or a decahydro-naphthalenyl,    wherein R 1  can be optionally substituted with 4 methyls, a C 1 -C 2  alkylene-6-membered heterocycloalkyl, or from 1 to 3 substitutents independently selected from the group consisting of: 
 C 1 -C 4  alkyl, methyl, tert-butyl, C(O)CH 3 , C(O)O—C 1 -C 4 alkyl, CH 2 -phenyl, a C 5 -C 6  cycloalkyl, Cl, Br, F, —CF 3 , —OH, —OCF 3 , and O—C 1 -C 6 alkyl,  
   and a pharmaceutically acceptable carrier.